The vertebrate renal proximal tubule is responsible for the excretory transport of a large number of potentially toxic chemicals, including, waste products of normal metabolism, drugs, environmental pollutants and drug and pollutant metabolites. These chemicals are handled by multiple specific, secretory transport systems that remove them from the blood and concentrate them in urine. At present little is known about the control of these transport systems. We are using comparative models (intact renal proximal tubules from teleost fish and mammalian renal slices and cells in culture) in combination with fluorescence microscopy (conventional and confocal), video imaging, intracellular microinjection and isolated membrane vesicle techniques to identify the physiologically relevant extracellular signals (hormones, metabolites, xenobiotics), and the intracellular signalling pathways involved in the control of xenobiotic excretion in renal proximal tubule. Our recent experiments show that all xenobiotic transport systems in isolated killifish renal proximal tubules are under control of protein kinase C (PKC). Transport mediated by the organic anion systems and by the multidrug resistance transporter (p- glycoprotein) fell when PKC was activated parmacologically and increased when PKC was inhibited. Moreover, dopamine, parathyroid hormone and endothelin-1 acting through their respective plasma membrane receptors and through PKC reduced transport mediated by the organic anion systems. Future work will focus on the membrane targets and intracellular signals involved.